EA029416B1 - Tablet comprising imatinib or a pharmaceutically acceptable salt thereof and process for the preparation thereof - Google Patents

Abstract

The invention relates to the field of pharmaceutics and medicine and concerns a tablet comprising imatinib or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the core of the tablet consists only of an active substance granulated by wet granulation without any excipients, and extragranular ingredient - a disintegrant and a glidant and/or lubricant, to a process for the preparation of such tablet and a process for the preparation of a pharmaceutical composition comprising imatinib or a pharmaceutically acceptable salt thereof without using excipients on the step of granulation, that provides fast disintegration while maintaining high stability of the tablets obtained.

Description

The invention relates to the field of pharmaceuticals and medicine and relates to tablets containing imatinib or its pharmaceutically acceptable salt as an active ingredient, while the core of the tablet consists only of the active substance granulated by the method of wet granulation without auxiliary substances and extragranular ingredients - disintegrant and sliding and / or a lubricant, a method for producing such a tablet, and a method for producing a pharmaceutical composition of imatinib or a pharmaceutically acceptable salt thereof Using the excipients in the granulation step that provides rapid disintegration while maintaining high strength of the resulting tablets.

029416

The invention relates to pharmaceutical compositions containing as the active component imatinib or its pharmaceutically acceptable salt, and methods for their preparation.

4 - [(4-Methyl-1-piperazinyl) methyl] -Y- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] benzamide, known as imatinib, The pharmaceutically acceptable salt and the method for its preparation were first disclosed in European patent application EP 0564409 A. Imatinib, in the form of a methanesulfonic acid salt, is known for its preparation with the trade name SPUSS®®. available on the market for the following indications: treatment of chronic myeloid leukemia, acute lymphoblastic leukemia with Philadelphia chromosome, myelodysplastic / myeloproliferative syndromes, advanced hypereosinophilic syndrome, as well as chronic eosinophilic leukemia, gastrointestinal stromal tumors, and chronic eosinophilic leukemia, gastrointestinal stromal tumors, and chronic eosinophilic leukemia, gastrointestinal stromal tumors, and chronic eosinophilic leukemia, gastrointestinal stromal tumors, and chronic eosinophilic leukemia, gastrointestinal stromal tumors, and chronic eosinophilic leukemia, gastrointestinal stromal tumors, and chronic eosinophilic leukemia, gastrointestinal stromal tumors, and chronic eosinophilic leukemia, gastrointestinal stromal tumors, and eroinophilic syndrome

Imatinib is prescribed orally to patients at a dose of up to 800 mg per day, depending on the condition of the patient. Initially, imatinib was on the market in the form of capsules in doses of 50 and 100 mg, which was very inconvenient for patients who had to take several capsules at a time. In the application EP 1501485 A1, tablets containing a large dose of imatinib and certain excipients, including at least one binder, at least one disintegrant, at least one lubricant and at least one lubricant, have been disclosed. The method for manufacturing a tablet disclosed in EP 1501485 A includes wet granulation of imatinib mixed with pharmaceutically acceptable excipients, which include a binder, followed by mixing the granulate thus obtained with a pharmaceutically acceptable auxiliary substances and pressing the mixture into a tablet.

The application EP 1762230 A1 discloses a method for preparing a pharmaceutical composition containing imatinib or a salt thereof using a dry granulation process. All examples in this application disclose the process of dry granulation of imatinib or its pharmaceutically acceptable salt together with at least one binder. The biggest disadvantage of the dry granulation process is the price of the equipment, which makes this technology expensive and consequently uncommon.

The aim of the present invention is to develop a new oral tablet containing imatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which can be made in a simpler way compared to methods known from the prior art without using expensive technologies. In addition, the tablet in accordance with the invention for the convenience of the patient should advantageously be characterized by a high content of the active ingredient. Thus obtained tablet is characterized by smaller size, which is good for patients who have problems with swallowing.

Surprisingly, it has been found that tablets containing imatinib or a pharmaceutically acceptable salt thereof in the core as an active substance can be made without the use of a binder. In addition, it has been unexpectedly discovered that tablets containing imatinib or a pharmaceutically acceptable salt thereof can be made by wet granulation with imatinib or a pharmaceutically acceptable salt thereof without using a binder. The tablets obtained by this method are characterized by better bioavailability, showing a shorter disintegration time. In addition, the core of the tablet in accordance with the invention is characterized by a high content of the active ingredient.

In accordance with the invention, the tablet contains imatinib or a pharmaceutically acceptable salt thereof as an active ingredient in the tablet core, while the tablet core consists only of imatinib or a pharmaceutically acceptable salt thereof, granulated by the wet granulation method without using any pharmaceutically acceptable excipient and extragranular ingredients - at least one disintegrant, at least one lubricant and / or lubricant.

The binder, which in the present invention is excluded from the auxiliary substances used, is a substance used to impart binding properties to bulk materials, as well as preserving the binding properties in the tablet after it is pressed. In the description of the invention, the terms binder and binding factor mean the same thing and can replace each other. Examples of binders are hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, povidone, and starch.

The tablet according to the invention preferably contains the active component, i.e. Imatinib or its pharmaceutically acceptable salt, in large quantities, preferably in an amount of from 55 to 93 wt.% in terms of the total mass of the tablet core, more preferably from 60 to 90%, most preferably from 65 to 85%. In one aspect of the invention, the tablet contains from 50 to 75% by weight of imatinib base, calculated on the total weight of the tablet, and at least one excipient that is not a binder. In a further aspect of the invention, the tablet core consists only of imatinib or a pharmaceutically acceptable salt thereof, at least one disintegrant, at least one lubricant and / or lubricant. A tablet in accordance with the invention preferably contains at least one

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disintegrant, not part of the granulate, preferably selected from the group comprising crospovidone, croscarmellose sodium, sodium carboxymethyl starch, and mixtures thereof. Disintegrant preferably ranges from 7 to 30 wt.% In terms of the total mass of the tablet core, more preferably from 10 to 25%, most preferably from 12 to 20%.

The tablet according to the invention preferably contains at least one lubricant and / or lubricant that is not part of the granulate. Sliding and lubricating substances can be mutually replaced, since they often exhibit both sliding and lubricating properties.

The glidant is preferably selected from the group consisting of colloidal silicon dioxide, calcium silicate, magnesium trisilicate, and mixtures thereof. The glidant is preferably from 0.1 to 10% by weight, based on the total mass of the tablet core, more preferably from 0.5 to 8%, most preferably from 1 to 5%.

The lubricant is preferably selected from the group comprising sodium stearyl fumarate, talc, magnesium stearate, calcium stearate, zinc stearate, and mixtures thereof. The lubricant is preferably from 0.1 to 5% by weight, calculated on the tablet core, more preferably from 0.5 to 4%, most preferably from 1 to 3%.

The tablet according to the invention contains as active ingredient imatinib or a pharmaceutically acceptable salt thereof, preferably imatinib methanesulfonate, also known as imatinib mesylate.

The concept of the core tablet in accordance with the invention means a tablet without a shell. In one aspect of the invention, the core of the tablet may be coated using known coating mixtures.

In addition, the invention includes a method for producing a pharmaceutical composition containing imatinib or a pharmaceutically acceptable salt thereof as an active ingredient, characterized in that it includes a wet granulation of imatinib or a pharmaceutically acceptable salt thereof without using any pharmaceutically acceptable excipient.

The method in accordance with the invention includes wet granulation of imatinib or a pharmaceutically acceptable salt thereof without the use of a binder, and without the use of any pharmaceutically acceptable excipient. In a further step, the method according to the invention preferably comprises mixing imatinib granulate or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable excipients.

The method according to the invention preferably comprises using the active component in an amount of from 55 to 93% by weight, calculated on the total weight of the pharmaceutical composition, more preferably from 60 to 90%, most preferably from 65 to 85%. In a preferred aspect of the method according to the invention, imatinib is used in the form of imatinib methanesulfonate, also known as imatinib mesylate. In one aspect of the invention, the method comprises using from 50 to 75% by weight of imatinib or a pharmaceutically acceptable salt thereof, calculated on the weight of imatinib free base, based on the total weight of the pharmaceutical composition.

The method in accordance with the invention in a preferred aspect of its implementation includes the use, in addition to the granulate, of pharmaceutically acceptable excipients, preferably at least one disintegrant, more preferably additionally at least one sliding and / or lubricant. In one aspect of the invention, the method exclusively includes the use of imatinib or a pharmaceutically acceptable salt thereof, as well as pharmaceutically acceptable excipients containing at least one disintegrant and at least one lubricant and / or lubricant.

The disintegrant is preferably selected from the group consisting of crospovidone, croscarmellose sodium, sodium carboxymethyl starch, and mixtures thereof. The disintegrant is preferably used in an amount of from 7 to 30% by weight, calculated on the total weight of the pharmaceutical composition, more preferably from 10 to 25%, most preferably from 12 to 20%.

The method in accordance with the invention preferably involves the use of at least one lubricant and / or lubricant. Sliding and lubricating substances can be mutually replaced, since they often exhibit both sliding and lubricating properties.

The glidant is preferably selected from the group consisting of colloidal silicon dioxide, calcium silicate, magnesium trisilicate, and mixtures thereof. The glidant is preferably used in an amount of from 0.1 to 10% by weight, calculated on the total weight of the pharmaceutical composition, more preferably from 0.5 to 8%, most preferably from 1 to 5%.

The lubricant is preferably selected from the group comprising sodium stearyl fumarate, talc, magnesium stearate, calcium stearate, zinc stearate, and mixtures thereof. The lubricant is preferably used in an amount of from 0.1 to 5% by weight, calculated on the total weight of the pharmaceutical composition, more preferably from 0.5 to 4%, most preferably from 1 to 3%.

In a preferred aspect of the invention, the method comprises the following steps:

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a) wet granulation of imatinib or its pharmaceutically acceptable salt without the use of any excipient, using purified water,

b) drying and preferably screening the granulate obtained in step a),

c) sifting and mixing auxiliary substances for use in non-granulate, including at least one disintegrant and at least one sliding and / or lubricating substance,

ά) mixing the mixture obtained in step c) with the granulate obtained in step b), e) pressing the mixture obtained in step ά) into a tablet.

In another preferred aspect of the invention, the method includes:

ΐ) granulation of imatinib methanesulfonate without the addition of any excipient, using a solvent, preferably purified water,

ΐΐ) mixing the granulate obtained in step (ΐ) with at least one disintegrant and according to

at least one lubricant and / or lubricant,

ΐΐΐ) pressing the mixture obtained in step (ΐΐ) into a tablet and, additionally, ίν) coating the tablet thus obtained with a coating.

The method according to the invention preferably comprises the preparation of a pharmaceutical composition in the form of a tablet core. Particularly preferably, the method according to the invention, which has been described above, comprises the preparation of a pharmaceutical composition in the form of a tablet core. The method according to the invention preferably comprises, in a further order, coating the pharmaceutical composition with a shell, preferably in the form of a tablet core, using known coating mixtures and standard equipment.

The granulation in paragraphs a) and ΐ) of the method according to the invention preferably includes the use of a fluidized bed granulator or a high-speed granulator, more preferably a high-speed granulator. The drying described in paragraph b) preferably includes the use of a tray or fluidized bed dryer. Mixing, described in paragraphs (c) and), as well as использование), preferably includes the use of a V-type mixer or hopper mixer. Tableting, described in paragraphs ά) and ΐΐΐ), preferably includes the use of an eccentric or rotary tablet press.

The invention is presented in the following examples, which in no way limit the scope of the invention.

Example 1

Granulate: [% / tablet]

Imatinib mesylate 82,13

Purified water ς.3.

Excipients not included in the granulate:

Croscarmellose sodium 13,57

Colloidal silicon dioxide 1.72

Sodium fumarate 1.55

Talc 1.03

A wet granulation of a weighed amount of imatinib mesylate was carried out using purified water. The granulate obtained in this way was dried on a tray dryer, and then sifted through a sieve with holes of 0.841 mm. Weighed amounts of auxiliary substances used in non-granulate, i.e., croscarmellose sodium, colloidal silicon dioxide, sodium fumarate and talc, were sieved through a sieve with holes of 0.595 mm and mixed for 3 minutes using a double cone mixer. The granulate and the mixture of excipients were mixed for 5 minutes in a double cone mixer, and then pressed into a tablet using a tablet press equipped with 16.5x7 mm oval punches. Received tablets weighing 582 mg.

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Example 2

[%/tablet]

Granulate:

Imatinib mesylate 88.78

Purified water δ.δ.

Excipients not included in the granulate:

Sodium carboxymethyl starch 5.35

Crosspovidone 2.23

Sodium fumarate 2.60

Colloidal silicon dioxide 1.04

The method was carried out in accordance with the description in example 1. Tablets weighing 538.4 mg were obtained.

Example 3

[%/tablet]

Granulate:

Imatinib mesylate 87.87

Purified water δ.δ.

Excipients not included in the granulate:

Sodium Carboxymethyl Starch 5.29

Crospovidone 2.21

Sodium fumarate 2.57

Colloidal silicon dioxide 1.03

Talc 1.03

Carried out the method of execution in accordance with the description in example 1. Received tablets weighing 544 mg.

Example 4

[%/tablet]

Granules: ‘

Imatinib mesylate 86.19

Purified water ts.z.

Excipients not included in the granulate:

Sodium carboxymethyl starch 8,12

Crosspovidone 2.16

Sodium fumarate 2.52

Colloidal silica 1.01

Carried out the method of execution in accordance with the description in example 1. Received tablets weighing 544 mg.

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Example 5

[%/tablet]

Granulate:

Imatinib mesylate 82,13

Purified water ς.8.

Excipients not included in the granulate:

Crosspovidone 13.57

Sodium fumarate 1.55

Colloidal silicon dioxide 1.72

Talc 1.03

Carried out the method of execution in accordance with the description in example 1. Received tablets weighing 582 mg.

Example 6

[%/tablet]

Granulate:

Imatinib mesylate 82,13

Purified water ς.8.

Excipients not included in the granulate:

Crosspovidone 13.57

Colloidal silicon dioxide 1.72

Talc 2.58

Carried out the method of execution in accordance with the description in example 1. Received tablets weighing 582 mg.

The tablets of examples 1-6 were subjected to physical research using standard methods. The results of these studies are presented in the table below.

Example one Example 2 Example 3 Example four Example five Example 6 Abrasion (%) 0.12 0.12 0.10 0.03 0.05 0.07 Hardness pills (kg / cm2) 10-11 12-14 10-19 17-19 ten 9-10

Additionally, the tablets of example 6 were coated by a standard method using a coating mixture consisting of hypromellose, macrogol, talc, red and yellow iron oxides. After coating the tablet weight was 593.5 mg. The disintegration time of the obtained coated tablets from Example 6 and tablets present on the market sold under the trade name Oyues® containing imatinib mesylate in the amount of 478 mg and microcrystalline cellulose, crospovidone, hypromellose, stearate as auxiliary substances was investigated using the standard method. magnesium and anhydrous colloidal silica coated with a mixture of red and yellow oxides of iron, macrogol, talc and hypromellose The table below.

Tablet coated shell, from example 6 Coated Oyues® tablet Decay time 5-6 minutes 7-8 minutes

Claims (15)

CLAIM 1. A tablet containing imatinib or a pharmaceutically acceptable salt thereof as an active ingredient in the tablet core, characterized in that the tablet core consists only of imatinib or a pharmaceutically acceptable salt thereof, granulated by wet granulation without using any pharmaceutically acceptable excipient and extragranular ingredients - at least one disintegrant, at least one sliding - 5 029416 and / or lubricant 2. The tablet according to claim 1, characterized in that the active ingredient is contained in an amount of from 55 to 93% by weight of the total weight of the tablet core, preferably from 60 to 90%, more preferably from 65 to 85%. 3. The tablet according to any one of claims 1, 2, characterized in that the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium carboxymethyl starch and a mixture thereof. 4. The tablet according to any one of claims 1 to 3, characterized in that the disintegrant is contained in the tablet core in an amount of from 7 to 30 wt.% Of the total mass of the tablet core, preferably from 10 to 25 wt.%, More preferably from 12 to 20 wt.%. 5. A tablet according to any one of claims 1 to 4, characterized in that the core of the tablet is coated. 6. A method of manufacturing a pharmaceutical composition containing as an active ingredient imatinib or a pharmaceutically acceptable salt thereof, characterized in that it includes a wet granulation of imatinib or a pharmaceutically acceptable salt thereof without using any pharmaceutically acceptable excipient. 7. The method according to claim 6, characterized in that it further comprises mixing imatinib granulate or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable extra granular excipients, preferably with at least one disintegrant and at least one lubricant and / or lubricant. 8. The method according to claim 6 or 7, characterized in that the active ingredient is used in an amount of from 55 to 93% by weight of the total weight of the pharmaceutical composition, preferably from 60 to 90%, more preferably from 65 to 85%. 9. The method according to claim 7 or 8, characterized in that the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium carboxymethyl starch and mixtures thereof. 10. The method according to any one of claims 7 to 9, characterized in that the pharmaceutical composition is the core of the tablet. 11. The method according to claim 10, characterized in that the disintegrant is used in an amount of from 7 to 30 wt.% Of the total mass of the tablet core, preferably from 10 to 25 wt.%, More preferably from 12 to 20 wt.%. 12. The method according to claim 10, characterized in that at a later stage the core of the tablet is coated. 13. A method of manufacturing a tablet according to any one of claims 1 to 5, characterized in that it includes wet granulation of imatinib or its pharmaceutically acceptable salt without the use of any pharmaceutically acceptable excipient. 14. The method according to claim 13, characterized in that it comprises ί) granulating imatinib methanesulfonate without adding any excipient using a solvent, ϊϊ) mixing the granulate obtained in step (ί) with at least one disintegrant and at least at least one lubricant and / or lubricant, ίίί) compressing the mixture obtained in step (ϊϊ) into a tablet. 15. The method according to 14, characterized in that it includes coating the obtained tablet shell.